Neuromuscular disorders are acquired or genetic conditions that affect some part of the neuromuscular system and are typically progressive. Neuromuscular disorders can be categorized as muscular dystrophies, peripheral motor neuron diseases, motor neuron diseases, neuromuscular junction diseases, myopathies, and metabolic diseases of the muscle. Examples of neuromuscular disorders include myotonic dystrophy, amyotrophic lateral sclerosis, and Parkinson's disease. Currently, there are no cures for most neuromuscular disorders. It is generally believed that novel treatments addressing one neuromuscular disorder may also help other neuromuscular disorders.
In general, genetic information from deoxyribonucleic acid (DNA) is transcribed by messenger RNA (mRNA) into proteins. Many neuromuscular diseases, including muscular dystrophies, are caused by genetic mutations that alter mRNA and their resultant proteins that control muscular function. MicroRNA (miRNA) are small, noncoding RNA that can bind to mRNA and post-transcriptionally block DNA- and mRNA-driven activities. As such, miRNA can be targeted to block the effects of genetic mutations, mRNA and resultant proteins that cause neuromuscular diseases. For example, increasing levels of certain miRNAs could be used to downregulate mRNA to treat neuromuscular disorders (see Alexander M S et al., (2015), Skeletal Muscle MicroRNAs: Their Diagnostic and Therapeutic Potential in Human Muscle Diseases, J Neuromusc Dis 2:1-11).
Abnormal levels of specific miRNAs, including lower levels of miR-29c, have been identified as risk factors for and contributors to neuromuscular disorders, such as Duchenne muscular dystrophy, myotonic dystrophy, and nemaline myopathy, Parkinson's disease and rapidly progressive amyotrophic lateral sclerosis. Thus, miR-29c has been proposed as both a blood-based biomarker of and potential therapeutic target for neuromuscular disease.
Notwithstanding the exciting new uses of miRNA, and in particular miR-29c, there have been ongoing barriers related to the delivery of miRNAs to the patient. While direct administration of miRNAs to patients can be challenging due to their inability to cross the gut barrier intact, other small molecules taken orally can influence miRNA activity, enabling the potential for safe and easily administered therapeutics to up- or down-regulate miRNA, which can post-transcriptionally alter gene expression (see Deiters (2010) Small molecule modifiers of the microRNA and RNA interference pathway AAPS J 12:51-60). Please see also Karius et al., MicroRNAs in Cancer Management and Their Modulation by Dietary Agents. Biochem Pharmacol 83:1591-1601 (2012). What is desired is the administration of a small molecule biochemical that can be used to upregulate and raise miR29C in a manner that is therapeutic to a patient suffering from a neuromuscular disease.